PROJECT SUMMARY/ABSTRACT The coevolution of hosts and parasites is mediated by genetic mutations that allow one side to gain an advantage over the other. As the host immune system bears the primary burden of responding to evolving parasites, it is expected to adapt or diversify in response to natural selection. However, recent population genetics analyses from a variety of animal taxa only partially bear out this hypothesis, revealing a paucity of adaptive evolution among innate immune gene repertoires relative to expectations. My recent work suggests that an appreciable proportion of genes associated with innate immune responses in taxa as broad as humans, insects and plants are pleiotropic, meaning that they also play unrelated roles in other organismal traits like development and the response to abiotic stress. This observation raises the possibility of temporal and evolutionary tension between the use of a gene product for developmental and immunological functions. Current coevolutionary theory largely fails to account for sources of genetic constraint on host defenses, impeding the translation of existing coevolutionary models into predictions for evolutionary dynamics at the molecular or system level. Moving forward, a major focus of research in my lab will be to explore the role of pleiotropic genetic architecture on the evolvability of host immune systems in response to parasite pressure. To tackle this long-term objective, my lab will employ several complementary approaches. Using transcriptome data, we will define the extent and dynamics of pleiotropy among developmental, stress, and immunological pathway genes in a variety of insect model species. We will perform genome-wide evolutionary genetics analyses in these insect species to quantify signatures of selection on pleiotropic and non-pleiotropic developmental, immunological, and stress response gene sets relative to null expectations. We will build mathematical models of immune pathway protein networks possessing different properties ? modularity, redundancy, complexity, pleiotropy ? and allow them to co-evolve with parasites, quantifying changes in fitness landscapes to better understand network structures that constrain or promote host adaptation. In parallel, we will run coevolution experiments using the flour beetle Tribolium castaneum and its natural parasites. We will manipulate the strength of pleiotropic antagonism among immunity and other processes in these experiments by limiting host-microbe interactions to a particular developmental stage or altering abiotic stress conditions, and then compare the evolutionary trajectories and genetic bases of host-microbe interaction outcomes. Together, these research avenues will provide insight into an array of fundamental questions about the extent of genetic pleiotropy among essential physiological processes, the influence of pleiotropy on coevolutionary dynamics, and the role of immune system architecture in host adaptation to parasite pressure. Gaining greater insight into the evolutionary forces that shape biological systems has important implications for predicting human pathogen evolution, understanding the origins of diseases like autoimmunity and sepsis, and designing therapeutic treatments that minimize side effects.